This revised Program Project grant proposal entitled. Mechanisms of Esophageal Carcinogenesis. seeks to define and elucidate the molecular mechanisms underlying squamous cell carcinogenesis in the esophagus with eventual translation to new strategies in diagnosis and therapy. Based upon historical interactive collaborations between the Project Leaders and usage of the Scientific Core Facilities, this program project focuses upon hypothesis-driven research that is innovative. The experience and expertise of the Project Leaders, in concert with the platforms provided by the Core Facilities, will result in enhancement of the research that would not be possible if the projects were independent of each other. Project 1 (Rustgi, Project Leader) will focus upon the biological roles of epidermal growth factor receptor (EGFR) overexpression in the early or precursor stages of esophageal carcinogenesis and their functional consequences. Project 2 (Herlyn, Project Leader) will emphasize the interplay of epithelial-stromal interactions, especially the EGF and TGFbeta receptor systems, and their influence on esophageal carcinogenesis. Project 3 (El-Deiry, Project Leader) will elucidate the role of the TRAIL apoptotic pathway in esophageal carcinogenesis. Importantly, the projects are further united by their utilization of unique organotypic cultures and genetically engineered mice that have esophageal epithelial specific gene expression, both developed by the Project Leaders. Three highly successful Core facilities are designed to provide esophageal cancer-specific services for the stimulation of collaborative research: Morphology, Molecular Biology/Gene Expression and Administrative. This Program Project has the unequivocal support of the University of Pennsylvania Cancer Center and Medical School and as such will foster interdisciplinary research that leads to a cooperative understanding of the molecular processes that form and regulate esophageal carcinogenesis. Finally, the Program Project is in concert with the NCI Progress Review Group for esophageal and stomach cancers.